The purpose of this project is to identify the determinants of type 2 diabetes, obesity, and other chronic diseases in the Pima Indians, and elucidate their natural history. Genetic and environmental risk factors for type 2 diabetes have been studied. The residents of the study area, approximately 5000 people, have participated in a longitudinal population study since 1965, allowing observations of the natural history of diabetes mellitus. Risk factors for obesity, hypertension, and nephropathy are also studied, along with the relationships of these diseases to diabetes and their effects on mortality rates. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. The roles of obesity, serum insulin concentrations, impaired glucose regulation, occupational and leisure-time physical activity and diabetes in relatives are assessed. Studies of the genetics of type 2 diabetes and obesity are described in project report # Z01 DK 69028 PECR. Recent work has focused on the incidence of type 2 diabetes in American Indian children, which has markedly increased in the last few decades. By virtue of absence of antibodies to GAD and lack of absolute insulin dependence, it was confirmed that diabetic Pima Indian children have only type 2 diabetes, not type 1 which is the common form in Caucasian children. The major risk factor is exposure to maternal diabetes in utero, the importance of which has not diminished over time despite improved recognition and treatment of diabetes in pregnancy. From the longitudinal measures of glycemia, it was shown that fasting and post-load plasma glucose (during an oral glucose tolerance test) are equivalent as predictors of microvascular disease and cardiovascular mortality. Greater sensitivity in identifying persons at high risk of hyperglycemia-associated adverse outcomes can be achieved by using lower levels of fasting glucose than usually recommended or by combining fasting and post-load glucose values. Diagnostic criteria developed in adults perform similarly in children, and hence can be recommended in studying the growing problem of youth-onset type 2 diabetes. On average, study subjects who develop type 2 diabetes gain weight for many years before onset, and then steadily lose weight. Weight loss is attenuated in those taking drug treatment for hyperglycemia. This weight loss must be considered in plans for clinical trials of weight control in diabetes.